Statin drugs, which are used to treat high cholesterol, have been reported to reduce breast cancer risk in some studies but not in others. Similarly, breast cancer recurrence might be influenced by statin use, but the evidence is mixed. As a result, the topic of statin use and its association with breast cancer is controversial. Now a new study has begun to describe how statins interact with breast cancer and which tumors might be treated effectively with statins.
Statin use and risk of breast cancer
Dietary cholesterol has been found to accelerate and promote mammary tumor formation in mice. Circulating cholesterol levels were observed to be reduced during tumor development (but not prior to tumor initiation) in one study, providing evidence for increased use of cholesterol by tumors. In other words, an increase in cholesterol might accelerate the development of breast tumors and increase their aggressiveness.
However, studies have reported contradictory results concerning the association between statin use and risk of breast cancer. Statins are classified either as lipophilic (e.g., Lipitor, Zocor, Mevacor, Lescol) or hydrophilic (Crestor, Pravachol), depending on the compound. A 2008 study reported that lipophilic statin use reduced the risk of triple negative breast cancer, however the results were not confirmed by subsequent studies. A large 2010 study that included 22,486 breast cancer cases concluded that there does not appear to be an association between lipophilic statin use and breast cancer risk in general or the risk of specific receptor subtypes. Any effect, if it exists at all, is likely much smaller than previous studies suggested, according to the authors.
Nevertheless, previous studies found associations between statin use and breast cancer for some women. One study reported that compared to non-users, obese women who used hydrophobic statins had a greatly increased risk of progesterone receptor negative (PR-) breast cancer, but not of progesterone receptor positive (PR+) tumors. Breast cancer risk was also found to be increased among overweight women who used hydrophobic statins for up to four years.
Statin use and risk of recurrence
While not all studies have reported an association, statin use might influence breast cancer recurrence. One study that included women with stage I to IV breast cancer found that while statin use did not affect the three-year overall survival of early stage breast cancer, it appeared to improve the outcome at more advanced stages (stage III and stage IV). Lipitor was the most used treatment among the study participants.
A study that included all 18,769 Danish women diagnosed with stage I-III invasive breast cancer between 1996 and 2003 reported that Zocor users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow up compared to women who did not use a statin. On the other hand, exclusive hydrophilic statin users were found to have approximately the same risk of breast cancer recurrence as women not prescribed a statin. The authors concluded that Zocor, a highly lipophilic statin, was associated with reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast cancer.
A small study that sought to examine whether statin therapy influences survival in patients with type 2 diabetes reported that diabetic breast cancer patients receiving statins to treat high cholesterol had better disease-free survival than patients not receiving any cholesterol management medication at diagnosis.
Latest research uncovers mechanism of action of statins
The new study referenced at the beginning of this news article helps explain the anticancer effects of statins and why they appear to be effective only in some women. The study was designed to investigate whether the removal of mutant p53 is sufficient to return breast cancer cells to a normal shape and structure, as well as the possible influence of statin drugs on this process.
p53 is a tumor suppressor protein that is encoded by tumor suppressor p53 gene. Activation of p53 results either in the death of the cell by apoptosis (programmed cell death) or survival of the cell by cell cycle arrest and DNA repair. Some foods that are chemopreventive also increase the expression of p53, thereby inducing cancer cell death. When functioning properly, p53 limits the growth of cells with incorrect numbers of chromosomes and prevents their progression toward cancer.
However, tumor suppressor p53 is the most frequently mutated gene in human tumors. These mutations don't just disrupt the normal functioning of p53, they often also endow p53 with new functions that promote, instead of inhibit, cancer formation. Mutant p53 frequently accumulates in cancer cells and promotes tumor cell invasion, as part of its acquisition of function. However, unlike many other cancers, p53 gene mutations are infrequent in breast cancer, occurring in up to one-third of breast tumors. In fact, p53 mutations are rare in early-stage estrogen receptor positive (ER+) breast cancer.
Breast cancer cells display highly disorganized morphology (shape and structure). To conduct the study, the authors used a three-dimensional culture technique to create a realistic tumor model. In the culture, noncancerous breast cells were induced to form spheroids similar to the cellular structures found in the human breast. Cells carrying mutant p53 grew in the misshapen, disorganized manner typical of breast cancer. Reducing levels of mutant p53 was found to be sufficient to return these breast cancer cells to a more normal morphology.
Further analysis demonstrated that the mevalonate pathway, a cholesterol-building pathway, was significantly upregulated by mutant p53. This pathway was shown to be both necessary and sufficient for the effects of mutant p53 on breast tissue architecture. Statin drugs lower cholesterol by inhibiting a step in the same pathway. When cells with mutant p53 were treated with statins, their disorganized, invasive growth was halted and some died. The authors conclude that the study findings imply that the mevalonate pathway may be a promising therapeutic target for tumors bearing mutations in p53. In a separate interview, study author Carol Prives of Columbia University said, "The data raises the possibility that we might identify subsets of patients whose tumors may respond to statins."
The bottom line
The fact that tumor suppressor p53 is not mutated in many breast cancers might explain why statin use influences breast cancer risk and survival inconsistently. Also, the observation that p53 mutations are rare in early-stage ER+ breast cancer could explain the finding that Lipitor appears to improve the outcome of stage III and stage IV breast cancer, but not stage I or stage II. Clearly, it is not currently possible to determine which breast cancer survivors could benefit from statin use. However, for those who need to take statins, lipophilic statins such as Zocor and Lipitor appear to be the best choice.