Hyder Tara, Marti Juan Luis Gomez, Nasrazadani Azadeh, Brufsky Adam M
University of Pittsburgh Physicians, Pittsburgh, PA 15213, USA.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Cancer Drug Resist. 2021 Jun 19;4(2):356-364. doi: 10.20517/cdr.2020.112. eCollection 2021.
Most breast cancers are hormone-receptor positive (HR). However, more women eventually die from HR breast cancer than from either HER2 or triple negative breast cancer. Endocrine therapies continue to be the mainstay of treatment. In 40% of these cases, recurrences in early-stage disease and progression in the metastatic setting are largely a function of the development of endocrine resistance. A multitude of mediators and pathways have been associated with endocrine resistance in breast cancer including the mevalonate pathway, which is integral to cholesterol biosynthesis. The mevalonate pathway and the downstream activation of associated cytoplasmic pathways including PI3K-AKT-mTOR and RAS-MEK-ERK have been known to affect cancer cell proliferation, cell survival, cell invasion, and metastasis. These are important mechanisms leading to the inevitable development of endocrine resistance in HR breast cancer. Statins are a class of drugs that inhibits HMG-CoA reductase, an enzyme in the mevalonate pathway that plays a central role in cholesterol production. and studies suggest that the role of statins in blocking the mevalonate pathway effectively disrupts downstream pathways involved in estrogen receptor expression and cellular processes such as cell survival, proliferation, stress, cell cycle, inhibition of apoptosis, and autophagy. Overcoming these key mechanisms heralds a role for statins in the prevention of endocrine resistance.
大多数乳腺癌是激素受体阳性（HR）。然而，最终死于HR乳腺癌的女性比死于HER2或三阴性乳腺癌的女性更多。内分泌疗法仍然是主要的治疗手段。在这些病例中，40%的早期疾病复发和转移性疾病进展在很大程度上是内分泌抵抗发展的结果。多种介质和途径与乳腺癌的内分泌抵抗有关，包括甲羟戊酸途径，它是胆固醇生物合成所必需的。已知甲羟戊酸途径以及相关细胞质途径（包括PI3K-AKT-mTOR和RAS-MEK-ERK）的下游激活会影响癌细胞的增殖、细胞存活、细胞侵袭和转移。这些是导致HR乳腺癌不可避免地产生内分泌抵抗的重要机制。他汀类药物是一类抑制HMG-CoA还原酶的药物，HMG-CoA还原酶是甲羟戊酸途径中的一种酶，在胆固醇生成中起核心作用。 和 研究表明，他汀类药物阻断甲羟戊酸途径的作用有效地破坏了参与雌激素受体表达和细胞存活、增殖、应激、细胞周期、抑制细胞凋亡和自噬等细胞过程的下游途径。克服这些关键机制预示着他汀类药物在预防内分泌抵抗方面的作用。
